1. Field of the Invention
The present invention is in the field of clinical neurology and relates to a method for preventing and/or treating memory and other cognitive impairments associated with aging, such as Age-Associated Memory Impairment (also known as Age-Related Cognitive Decline) and other age-related changes in cognitive function.
2. Description of the Related Art
There are many memory-related conditions for which therapeutic treatments have been under investigation, such as methods to enhance memory or to treat memory dysfunction. Certain types of memory dysfunction are believed to be linked to the aging process, as well as to neurodegenerative diseases such as Alzheimer's disease. Memory impairment can also follow head trauma or multi-infarct dementia. Many compounds and treatments have been investigated which can enhance cognitive processes and improve memory and retention abilities.
For example, the compound piracetam has been prescribed for treatment to enhance memory (Giurgea et al, Arch. Int. Pharmacodyn. Ther. 166, 238 (1967). U.S. Pat. No. 4,639,468 to Roncucci et al describe the use of the compound milacemide for treatment of memory impairment. Further investigation of milacemide has documented the memory-enhancing capabilities of milacemide in human subjects B. Saletu et al. Arch. Gerontol. Geriatr. 5, 165-181 (1986)!. Bodor (U.S. Pat. No. 5,296,483) teaches a new approach for delivering drugs to the brain using the redox system. Specifically, the primary, secondary, or tertiary functions of centrally acting amines are replaced with a dihydropyridine/pyridinium salt redox system, and the resulting quaternary compounds provide site-specific and sustained delivery to the brain. Upon delivery to the brain, the compound is oxidized to a form which cannot readily pass the blood-brain barrier and hence is "locked" in the brain.
Riekkinen et al. (U.S. Pat. No. 5,434,177) teaches the use of .alpha.-2-receptor antagonist imidazole derivatives for the treatment of age related cognitive disorders. Cordi et al. (U.S. Pat. Nos. 5,260,324 and 5,208,260) teach a composition containing D-cycloserine and D-alanine, and vinyl glycine derivatives, for memory enhancement or treatment of cognitive disorders, respectively.
Thiamine (vitamin B-1) is an essential nutrient and an indispensable component in the oxidation of glucose, which is the main source of cellular energy in the central nervous system (CNS). With respect to its role in cellular energy production, thiamine, in its biologically active diphosphate form, acts as a coenzyme in two mitochondrial enzyme complexes--the pyruvate dehydrogenase (PDH) and the .alpha.-keto glutarate dehydrogenase (.alpha.-KGDH) complexes. PHD and .alpha.-KGDH must be sufficiently active to provide glucose oxidation rates necessary for cellular energy requirements. If thiamine availability is inadequate to attain this required enzyme activity level, then the energy-yielding metabolism derived from the oxidation of glucose will be reduced and cell integrity may be jeopardized. This is particularly true in the CNS where cells are more dependent on oxidative glucose metabolism for energy than are cells in the rest of the body.
In addition to its crucial role in cellular energy production, thiamine is: 1) an essential cofactor for activity of transketolase, an enzyme involved in biosynthetic reactions; 2) required for normal conduction of electrical impulses along nerve fibers (Cooper J. R., Pincus J. H.; The role of thiamine in nervous tissue; Neurochem. Res., 4:223-239, 1979); and 3) implicated in the synthesis and neural release of acetylcholine (Eder L., Dunant Y.; Thiamine and cholinergic transmission in the electric organ of torpedo; J. Neurochem, 35:1278-1296, 1980), a neurochemical that plays an important role in learning and memory.
Intake of thiamine in humans is accomplished by consumption of thiamine-containing foods and of commercial vitamin preparations. The recommended dietary allowance (RDA) for thiamine in the United States is roughly 0.5 mg per 1000 consumed calories.
Thiamine in its water soluble form is absorbed by the small intestine via two processes, depending upon its concentration in the intestinal lumen (Rindi G., Ventura U.; Thiamine intestinal transport; Physiol. Rev., 52:821-827, 1972; Hoyunpa A. M., Strickland R., Sheehan J. J., Yarborough G., Nichols S.; Dual system of intestinal transport of thiamine in humans; J Lab Clin Med., 99.701-708, 1982). At low concentrations (&lt;2 micromolar) a saturable, energy-dependent active transport mechanism operates against a concentration gradient. At high concentrations (&gt;2 micromolar) the vitamin is absorbed by passive diffusion, down a concentration gradient. In humans, there is little increase in urinary thiamine excretion at oral dosages in excess of 0.5 mg (Morrison A. B., Campbell J. A.; Factors influencing the excretion of oral test doses of thiamine and riboflavin by human subjects; J. Nutr., 72.435-444, 1960), suggesting that passive diffusion of this water soluble vitamin across the intestinal wall is not significant. However, more recent evidence suggests that high oral doses of water-soluble thiamine does produce a parallel increase in its absorption (Meador K., Loring D., Nichols M., Zamrini E., et al.; Preliminary findings of high dose thiamine in dementia of Alzheimer's type; J. Geriatr. psychiatry Neurol., 6:222-229, 1993).
Transport of water soluble thiamine across the blood brain barrier also involves two processes (Greenwood J., Love E. R., Pratt O. E.; Kinetics of thiamine transport across the blood-brain barrier in the rat; J. Physiol., 327:95-103, 1982; Reggiani C., Patrini C., Rindi G.; Transport of thiamine and thiamine monophosphate from plasma to different brain regions of the rat; Brain Res., 293:319-327, 1984): a saturable active carrier-mediated mechanism and a non-saturable mechanism which may also involve a carrier molecule (Greenwood J., Pratt O. E.; Comparison of the effects of some thiamine analogues upon thiamine transport across the blood-brain barrier of the rat; J. Physiol, 369.79-91, 1985). Entry of thiamine into brain cells is governed by an active transport system which is distinct from those that control its passage across the blood-brain barrier (Sharma S. K., Quastel J. H.; Transport and metabolism of thiamin in rat brain cortex in vitro; Biochem. J., 94. 790-800, 1965; Spector R. O.; Thiamine transport in the central nervous system; Am J. Physiol, 230:1101-1107, 1976).
The relationship between thiamine and aging is not fully understood. In free-living persons, both calorie and thiamine intake diminish with advancing age, but the USRDA intake ratio of 0.5 mg thiamine/1000 calories is maintained or exceeded in all age groups studied by Iber and coworkers (Iber F. L., Blass J. P., Brin M., Leevy C. M.; Thiamin in the elderly, relation to alcoholism and neurological degenerative disease; Am. J. Clin. Nutr., 6:1067-1082, 1982). However, even though existing data shows that thiamine intake is adequate among the aged, there is also evidence to suggest that aging is associated with changes in thiamine utilization and metabolism. Biochemical measures of thiamine function done on free-living elderly people in England revealed abnormalities suggesting severe thiamine deficiency in 15% and marginal deficiency in 53% of 118 persons studied (Griffiths L. L., Brocklehurst J. C., Scott D. L., Marks J., Blackley J.; Thiamine and ascorbic acid levels in the elderly; Gerontol. Clin., 9:1-10, 1967). Another study showed that 45% of 75 persons living in an old age home in Finland showed biochemical evidence of marginal thiamine deficiency (Roine P., Koivula L. I., Pekkarinen M. O.; Plasma vitamin C level and erythrocyte transketolase activity compared with vitamin intakes among old people in Finland; Nutrition, 4:116-120, 1972). Other studies have shown reduced excretion of thiamine in elderly humans, suggesting that its levels in tissues are lowered with age (Rafsky H. A., Newman B.; Vitamin B-1 excretion in acid; Gastroenterology, 1. 1943; Rafsky M. A., Newman B., Jolliffe N.; Relationship of gastric acidity to thiamine excretion in aged; J. Lab. Clin. Med., 32:118-123, 1947).
Animal experiments further indicate changes in thiamine needs, as well as in thiamine utilization and metabolism, with aging. These animal experiments have demonstrated that: 1) old rats require more thiamine per gram of consumed food than young rats (Mills C. A., Cottingham E., Taylor E.; Effect of advancing age on dietary thiamine requirements; Arch. Biochem., 9:221-227, 1946); 2) transport of thiamine across the intestine is significantly lower in old rats compared to younger rats (Lazarov J.; Changes in the resporption and the phosphorylation of thiamine in rats in relation to age; J. Exp. Gerontol, 12:75-79, 1977); and 3) thiamine deficiency produces a larger decrease in the activity of .alpha.-KGDH (used in glucose oxidation) in the brains of old mice than in young mice (Freeman G. B., Nielsen P. E., Gibson G. E.; Effect of age on behavioral and enzymatic changes during thiamine deficiency; Neurobiol. Aging, 8.429-434, 1987). These data suggest that 1) thiamine intake requirements increase with aging; 2) the transport of thiamine from the intestine to the bloodstream is decreased with advancing age; 3) with aging, thiamine-dependent enzymes in the brain have an increased sensitivity to the effects of thiamine deficiency (i.e., enzyme activity is reduced by a lesser degree of thiamine deficiency in the aged than in the young).
From all of the above, it may be inferred that defective thiamine transport across the intestine may be a contributing factor in the age-related increase in thiamine requirements in relation to the amount of food consumed, while defective transport of thiamine from the blood to the brain may be an explanation for the age-related increase in thiamine deficiency sensitivity of thiamine-dependent enzymes in the brain. Accordingly, defective active transport of thiamine, whether across the intestine, the blood-brain barrier (BBB), or into brain cells, which results from the aging process, may be an important factor in the decline of memory function commonly associated with aging (Larrabee G. J., McEntee W. J., Crook T. H.; Age-Associated Memory Impairment; In cognitive Disorders: Pathophysiology and Treatment, E. R. Gamzu, W. H. Moos, L. J. Thal. (Eds) Marcel Dekker Inc, 1992; Larrabee and Crook 1994).
A connection between this age-related loss of memory abilities and abnormal thiamine function is suggested by the qualitative similarities in neuropsychological impairments demonstrated in healthy elderly persons and in younger patients with Korsakoff's disease, a learning and memory disorder linked to thiamine deficiency. Both groups perform poorly on tasks that require divided attention and both exhibit short-term memory deficits that may be due to deficient information processing (Craik; The nature of the age decrement in performance on dichotic listening tasks; Q. J. Exp. Psychol. 227-240; 1965; Glosser G., Butters N., Samuels I.; Failure of information processing in patients with Korsakoff's syndrome; Neuropsychology, 14:327-334, 1976; Butters N., Cermak L.; Alcoholic Korsakoff's syndrome: An information-processing approach to amnesia; Academic Press, New York, 1980). Furthermore, Korsakoff patients show specific deficits in performance on standardized psychometric tests that are particularly sensitive to the effects of aging. These tests include the Digit-Symbol subtest of the Wecshler Adult Intelligence Scale (Wechsler D.; Wechsler Adult Intelligence Scale; The Psychological Corporation, New York, 1955) and the Logical Memory, Visual Reproduction, and Associative Learning subtests of the Wechsler Memory Scale (Hulicka, I. M.; Age differences in Wechsler Memory Scale scores; J. Genetic Phsycol. 109:135-145; 1966).
Impaired active transport of thiamine may also play a role in the pathogenesis of age-related neurodegenerative disorders. For instance, Alzheimer's disease (AD) increases in frequency with advancing age, and a number of studies have shown that the activity of all thiamine-dependent enzymes is decreased in the brains of patients with AD at death (Perry E. K., Perry R. H., Tomlinson B. E., Blessed G., Gibson P. H.; coenzyme-A acetylating enzymes in Alzheimer disease: possible cholinergic compartment of pyruvate dehydrogenase; Neurosci. Lett., 18:105-110, 1980; Gibson G. E., Sheu R. F., Blass J. P., et al.; Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease; Arch Neurol., 45:836-840, 1988; Butterworth R. F., Besnard A.-M.; Thiamine-dependent enzyme changes in temporal cortex of patients with Alzheimer's disease; Metab. Brain Dis., 5:179-184,1990). More recently, significant decreases in the activity of .alpha.-KGDH in histologically normal skin fibroblasts of patients with familial AD have been reported (Sheu K.-F. R., Cooper A. J. L., Koike K., Koike M., et al.; Ann. Neurol., 35:312-318, 1994).
If age-related impairments of central nervous system function result from age-related changes in the active transport of thiamine, then attempts to correct these changes would be important in the overall effort to improve the quality of life of the elderly. Over the years, a number of studies and strategies have been designed to investigate the age-related changes in thiamine utilization and metabolism. Some studies have attempted to compensate for the age-related changes in water-soluble thiamine utilization and metabolism associated with people suffering from AD. None of these investigations have provided successful results over periods of a year or more. In a short-term clinical trial, AD patients treated daily with 3 grams of oral thiamine HCl over a period of three months showed a small, but statistically significant, improvement in performance on a single test of cognition compared to their performance during treatment with a placebo (Blass J. P., Gleason P., Brush D., et al.; Thiamine and Alzheimer's disease; Arch Neurol., 45:833-835, 1988). When this same treatment was given for more than one year, however, the small cognitive improvement seen in the 3 month trial failed to persist (Nolan K. A., Black R. S., Sheu K. F. R., et al.; A trial of thiamine in Alzheimer's disease; Arch Neurol., 48:81-83, 1991). More recently, Meador et al. (Meador K., Loring D., Nichols M., Zamrini E., et al.; Preliminary findings of high dose thiamine in dementia of Alzheimer's type; J. Geriatr. psychiatry Neurol., 6:222-229, 1993) treated a group of AD patients with higher doses of oral thiamine HCl. After taking 4-8 grams per day AD patients demonstrated a trend of improved performance on cognitive measures when compared with patient performance at baseline. However, this study did not show such improvement when comparisons were made with task performances following treatment with placebo.
Several lines of evidence suggest that changes in nervous system function which occur as an effect of aging may be related to abnormalities in the utilization and/or metabolism of thiamine. In this regard, most of the abnormalities are probably in the transport of thiamine from intestine to blood and from blood to brain.
No researcher has investigated a long term method for preventing or treating and ameliorating the memory and cognitive disorders and other nervous system impairments associated with aging, including Age-Associated Memory Impairment (also known as Age-Related Cognitive Decline) and other age-related cognitive impairments.